In Situ Forming Implants Research Articles

In-situ forming implants for dual controlled release of chlorhexidine and ibuprofen for periodontitis treatment: Microbiological and mechanical key properties

In-situ forming implants (ISFI) which simultaneously release an antimicrobial and anti-inflammatory drug in a controlled manner offer an interesting potential for local periodontitis treatment. In this study, poly(lactic-co-glycolic acid) (PLGA)-based implants loaded with chlorhexidine and ibuprofen were investigated, in particular with respect to their antimicrobial and mechanical key properties. PLGA (Resomer RG 502H) was dissolved in N-methyl pyrrolidone (NMP). Chlorhexidine dihydrochloride and ibuprofen (free acid) were added as well as acetyltributyl citrate (ATBC) as plasticizer and hydroxypropyl methylcellulose (HPMC, Methocel, E50) as adhesion enhancer. Upon contact with aqueous fluids, the NMP diffuses out and water into the formulation, causing polymer precipitation and drug entrapment. The antimicrobial activity against periodontal pathogens was studied using the agar-well diffusion test, time-kill studies and growth curve method. The syringeability of the liquid formulations and mechanical key properties of the in-situ formed implants were investigated using a texture analyzer. A commercially available gel used for local periodontitis treatment, loaded with chlorhexidine dihydrochloride and chlorhexidine digluconate (Chlo-site) was studied for reasons of comparison. Importantly, the investigated ISFIs showed a strong and rapid antibacterial activity against all the selected pathogens, while maintaining suitable mechanical properties. The simultaneous release of ibuprofen did not reduce the desired antimicrobial effect of chlorhexidine.

Optimization of injectable PLGA in-situ forming implants of anti-psychotic risperidone via Box-Behnken Design

The current study aims to develop in-situ forming implants (ISFI) of anti-psychotic risperidone to customize schizophrenia therapy. Non-adherence to treatment is the most prevalent unsuccessful clinical outcome in schizophrenic patients. Poly(lactic-co-glycolic acid) (PLGA) was utilized to prepare ISFI using various solvents having different drug solubilization capacity. 33 Box-Behnken Design (BBD) was used to study the effects of independent variables; lactide concentration (A), solvent type (B) and solvent/polymer ratio (S/P) (C) on burst release after 6h (Y1), cumulative release after 40 days (Y2) and injectability time (Y3). Statistical analysis was followed by optimization process to minimize burst release and injectability time with targeted cumulative release to 50% at 40 days. BBD results represented the critical impacts of increasing lactide and PLGA concentrations on reducing drug burst and percent release. Rapid ISFI solidification using DMSO supported the high dispersed drug encapsulation and sustained release. Triacetin demonstrated a lag time between formulation injection and solidification that negatively affected the studied responses. The optimized formulation manifested burst (8.1%), cumulative release (51.08%) and 18 s for injection by mixing PLGA (75:25) and DMSO (S/P = 2.851). Compared with injectable commercial microspheres, ISFI emphasized their potential to enhance compliance and eliminate costs issues of additional oral therapy.

In situ forming implants exposed to ultrasound enhance therapeutic efficacy in subcutaneous murine tumors

In situ forming implants (ISFIs) allow for a high initial intratumoral concentration and sustained release of the chemotherapeutic. However, clinical translation is impeded primarily due to limited drug penetration from the tumor/boundary interface and poor intratumoral drug retention. Therapeutic ultrasound (TUS) has become a popular approach for improving drug penetration of transdermal devices and increasing cellular uptake of nanoparticles. These effects are driven by the mechanical and thermal bioeffects associated with TUS. In this study, we characterize the released drug penetration, retention, and overall therapeutic response when exposing ISFI to the combination of the mechanical and thermal effects of TUS (C-TUS). ISFIs were intratumorally injected into subcutaneous murine tumors then exposed to C-TUS (exposure: 5 min, duty factor: 0.33, frequency: 3 MHz, intensity: 2.2 W/cm2, pulse duration: 2 ms, pulse repetition frequency: 165 Hz, effective radiating area: 5 cm2, energy delivered: 896 J, time average intensity: 0.88 W/cm2). Tumors treated with the combination of ISFI + C-TUS demonstrated a 2.5-fold increase in maximum drug penetration and a 3-fold increase in drug retention at 5- and 8-days post-injection, respectively, compared to ISFIs without TUS exposure. These improvements in drug penetration and retention translated into an enhanced therapeutic response. Mice treated with ISFI + C-TUS showed a 62.6% reduction in tumor progression, a 50.0% increase in median survival time, and a 26.6% increase in necrotic percentage compared to ISFIs without TUS exposure. Combining intratumoral ISFIs with TUS may be beneficial for addressing some long-standing challenges with local drug delivery in cancer treatment and may serve as a viable noninvasive method to improve the poor clinical success of local drug delivery systems.

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

P-glycoprotein (Pgp), a member of the ATP-binding cassette family, is one of the major causes of multidrug resistance in tumors. Current clinical treatments to overcome MDR involve the co-delivery of a Pgp inhibitor and a chemotherapeutic. A concern for this treatment that has led to varied clinical trial success is the associated systemic toxicities involving endogenous Pgp. Local drug delivery systems, such as in situ forming implants (ISFIs), alleviate this problem by delivering a high concentration of the drug directly to the target site without the associated systemic toxicities. ISFIs are polymeric drug solutions that undergo a phase transition upon injection into an aqueous environment to form a solid drug eluting depot allowing for a high initial intratumoral drug concentration. In this study, we have developed an ISFI capable of overcoming the Pgp resistance by co-delivering a chemotherapeutic, Doxorubicin (Dox), with a Pgp inhibitor, either Pluronic P85 or Valspodar (Val). Studies investigated in vitro cytotoxicity of Dox when combined with either Pgp inhibitor, effect of the inhibitors on release of Dox from implants in PBS, in vivo Dox distribution and retention in a subcutaneous flank colorectal murine tumor, and therapeutic response characterized by tumor growth curves and histopathology. Dox + Val showed a 4-fold reduction in the 50% lethal dose (LD50) after 48 hours. Concurrent delivery of Dox and Val showed the greatest difference at 16 days post injection for both Dox penetration and retention. This treatment group had a 5-fold maximum Dox penetration compared to Dox alone ISFIs (0.53 ± 0.22 cm vs 0.11 ± 0.11 cm, respectively, from the center of the ISFI). Additionally, there was a 3-fold increase in normalized total intratumoral Dox intensity with the Dox + Val ISFIs compared to Dox alone ISFIs (0.54 ± 0.11 vs 0.18 ± 0.09, respectively). Dox + Val ISFIs showed a 2-fold reduction in tumor growth and a 27.69% increase in necrosis 20 days post-injection compared to Dox alone ISFIs. These findings demonstrate that co-delivery of Dox and Val via ISFI can avoid systemic toxicity issues seen with clinical Pgp inhibitors.

Effect of Polymer Permeability and Solvent Removal Rate on In Situ Forming Implants: Drug Burst Release and Microstructure.

To explore the mechanism of drug release and depot formation of in situ forming implants (ISFIs), osthole-loaded ISFIs were prepared by dissolving polylactide, poly(lactide-co-glycolide), polycaprolactone, or poly(trimethylene carbonate) in different organic solvents, including N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and triacetin (TA). Drug release, polymer degradation, solvent removal rate and depot microstructure were examined. The burst release effect could be reduced by using solvents exhibit slow forming phase inversion and less permeable polymers. Both the drug burst release and polymer depot microstructure were closely related to the removal rate of organic solvent. Polymers with higher permeability often displayed faster drug and solvent diffusion rates. Due to high polymer-solvent affinity, some of the organic solvent remained in the depot even after the implant was completely formed. The residual of organic solvent could be predicted by solubility parameters. The ISFI showed a lower initial release in vivo than that in vitro. In summary, the effects of different polymers and solvents on drug release and depot formation in ISFI systems were extensively investigated and discussed in this article. The two main factors, polymer permeability and solvent removal rate, were involved in different stages of drug release and depot formation in ISFI systems.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

In-situ forming implants loaded with chlorhexidine and ibuprofen for periodontal treatment: Proof of concept study in vivo.

Control of infection and inflammation is crucial for the success of periodontal treatment. In this study, in-situ forming implants (ISFI) loaded with chlorhexidine dihydrochloride (CHX) and ibuprofen (IBU) were developed and tested to optimize periodontal treatment outcomes. Release profiles were promising. Exposure to 1.5% and 5.3% CHX-IBU loaded ISFI's release media decreased significantly the P. gingivalis growth up to 20-fold and 35-fold, respectively, after 48 h (p < 0.05). The metabolic activity assay of gingival epithelial cells (EC) demonstrated 1.5% CHX-IBU-loaded ISFI to be non-toxic, therefore, it was selected for further experimentation. Furthermore, significant down-regulation of TNF-α release (34% at 6 h and 43% at 24 h, p < 0.05) in P. gingivalis lipopolysaccharide (Pg-LPS) stimulated EC exposed to 1.5% CHX-IBU ISFI release medium was demonstrated by ELISA. In vivo, 1.5% CHX-IBU ISFI was injected into the periodontal pocket in an experimental periodontitis mouse model and the reduction in inflammation and improvement in periodontal wound healing was evaluated through inflammatory cell scoring and histomorphometry at 7- and 15-days post-treatment. The results indicate that CHX-IBU loaded ISFI could be efficient as adjuvant to periodontal therapy for the control of infection and inflammation. Moreover, other (e.g., pro-regenerative) drugs could be incorporated into ISFI to further improve periodontal treatment outcomes.

Noninvasive characterization of in situ forming implant diffusivity using diffusion-weighted MRI

In situ forming implants (ISFIs) form a solid drug-eluting depot, releasing drug for an extended period of time after a minimally-invasive injection. Clinical use of ISFIs has been limited because many factors affect drug release kinetics. The aim of this study was to use diffusion-weighted MRI (DWI) to noninvasively quantify spatial-temporal changes in implant diffusivity in situ. ISFIs were formed using poly(lactic-co-glycolic) acid, with a molecular weight of either 15 kDa or 52 kDa, and fluorescein as the mock drug. Drug release, polymer erosion, polymer degradation, and implant diffusivity were analyzed in vitro over 21 days. DWI was also performed in vivo over 5 days. Spatial diffusivity maps of the implant were generated using DWI data. Results showed constant diffusivity at the implant shell ((1.17 ± 0.13) × 10−3 mm2/s) and increasing diffusivity within the interior over time (from (0.268 ± 0.081) × 10−3 mm2/s during day 1 to (1.88 ± 0.04) × 10−3 mm2/s at 14 d), which correlated with increasing porosity of the implant microstructure. Implants formed in vivo followed the same diffusivity trend as those in vitro. This study validates the use of DWI to provide novel functional information about implant behavior through its ability to noninvasively characterize transport properties within the implant both in vitro and in vivo.

Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

Vascularized composite allotransplantation (VCA), such as hand and face transplantation, is emerging as a potential solution in patients that suffered severe injuries. However, adverse effects of chronic high-dose immunosuppression regimens strongly limit the access to these procedures. In this study, we developed an in situ forming implant (ISFI) loaded with rapamycin to promote VCA acceptance. We hypothesized that the sustained delivery of low-dose rapamycin in proximity to the graft may promote graft survival and induce an immunoregulatory microenvironment, boosting the expansion of T regulatory cells (Treg). In vitro and in vivo analysis of rapamycin-loaded ISFI (Rapa-ISFI) showed sustained drug release with subtherapeutic systemic levels and persistent tissue levels. A single injection of Rapa-ISFI in the groin on the same side as a transplanted limb significantly prolonged VCA survival. Moreover, treatment with Rapa-ISFI increased the levels of multilineage mixed chimerism and the frequency of Treg both in the circulation and VCA-skin. Our study shows that Rapa-ISFI therapy represents a promising approach for minimizing immunosuppression, decreasing toxicity and increasing patient compliance. Importantly, the use of such a delivery system may favor the reprogramming of allogeneic responses towards a regulatory function in VCA and, potentially, in other transplants and inflammatory conditions.

Isosorbide‐based polysebacates as polymeric components for development of in situ forming implants

In situ forming implants (ISFIs) appear to be a convenient drug delivery system, alternative to conventional preformed implants and microparticles for parenteral drug delivery applications. It has been shown that they offer several advantages including easy and minimally invasive application, potential for local/site‐specific drug delivery that allows reduction of side effects associated with systemic administration of drug. A few ISFI formulations based on poly(α‐hydroxy acids), solidifying by solid phase separation, are currently commercially available. In this work, polyesters based on sebacic acid, isosorbide, and optionally 1,2‐propanediol were synthesized and characterized. Poly(isosorbide sebacate‐co‐1,2‐propylene sebacate) (PISEBPG) was chosen as an essential constituent of new ISFI formulations dedicated to controlled release of doxycycline hyclate (DOXY). Basic characteristics of new ISFI formulations were investigated. In particular, the influence of addition of a relatively hydrophobic cosolvent (triacetin, TA) to a more hydrophilic 1‐methyl‐2‐pyrrolidone (NMP) as well as the presence of calcium carbonate (CAC) on the morphology of resulted depots and DOXY release profile was evaluated. Scanning electron microscopy (SEM) analysis revealed that the presence of TA resulted in more porous morphology of the depots. DOXY has been releasing continuously from depots in vitro within 12 weeks depending on the composition. The release profile of the PISEBPG‐based formulation containing CAC indicates that it could be useful where short‐term (up to 14 d), rapid release of the antibiotic is required, while formulation without CAC, where after 21 days about 50% of the drug loaded may still be available for release, may be better for the long‐term delivery of DOXY.

Comparison of in-situ forming composite using PLGA-PEG-PLGA with in-situ forming implant using PLGA: In-vitro, ex-vivo, and in-vivo evaluation of naltrexone release

An in-situ forming composite (ISFC) of naltrexone (NTX) was prepared using PLGA-PEG-PLGA (triblock) and N-methyl-2-pyrrolidone (NMP) for decreasing the initial burst release. The supercritical CO2 method was used to achieve the ring-opening polymerization of the triblock. The Box-Behnken design was used to achieve the minimal initial burst release of NTX in the in-vitro release medium. In-vitro, ex-vivo, and in-vivo studies of the ISFC were compared with an in-situ forming implant (ISFI) composed of copolymer PLGA 504H. The equivalency of ISFC and Vivitrol® were compared by sampling the concentration of NTX in rabbit blood. The results of the in-vitro release evaluation showed that the initial burst release for the ISFC (5.69 ± 0.27%) was significantly lower than that for the ISFI (17.45 ± 1.07%). The Cmax of NTX (15.16 ± 2.46 ng/mL) from the ISFC was significantly (p < 0.05) lower than that of the ISFI (24.46 ± 2.9 ng/mL) and Vivitrol® (21.11 ± 2.89 ng/mL). The bioavailability and the range of serum concentration of NTX for the ISFC formulation was similar to that of Vivitrol®. The results suggested that the ISFC could be used as a new type of sustained-release formulation with a smaller initial burst release than the ISFI.

In-vitro, ex-vivo, and in-vivo evaluation of buprenorphine HCl release from an in situ forming gel of PLGA-PEG-PLGA using N‑methyl‑2‑pyrrolidone as solvent

An in situ forming gel (ISFG) of buprenorphine (BP) was prepared using PLGA-PEG-PLGA (triblock) and N‑methyl‑2‑pyrrolidone as solvent for decreasing the initial burst release. Supercritical CO2 method was used for ring opening polymerization of triblock. The optimum formulation of ISFG was achieved based on a minimum initial burst release of BP in the in-vitro release media using Box-Behnken design. In-vitro, ex-vivo, and in-vivo studies of ISFG were compared with an in situ forming implant (ISFI) composed of copolymer PLGA 504H (similar to RBP-6000). The initial burst release from in vitro media for the ISFG (6.19 ± 0.31%) was significantly lower than that for the ISFI (13.45 ± 1.14%) because the thermosensitive property of the triblock and hydrogen bonding between the NMP molecules and the PEG of the triblock prevented the NMP from diffusing rapidly into the release medium. The Cmax of BP (6.95 ± 0.98 ng/mL) from the ISFG was significantly (p < 0.05) lower than those from the ISFI (8.19 ± 1.02). Furthermore, the AUC, the range of serum concentration (C) of BP for the ISFG (AUC = 2721.38 ± 69, C = 1.87–7.12) formulation were similar to those for ISFI (AUC = 2727.36 ± 71, C = 1.75–10). The results suggest that the ISFG can be used as a new type of sustained-release injection formulation with a smaller initial burst release than the ISFI.

Chemotherapeutic Efficacy of Implantable Antineoplastic-Treatment Protocols in an Optimal Mouse Model for Human Ovarian Carcinoma Cell Targeting.

The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan–Poly(vinylpyrrolidone)–Poly(N-isopropylacrylamide) (C–P–N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C–P–N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(N-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM’s) within the cross-linked C–P–N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.

Poly(isosorbide succinate)-based in situ forming implants as potential systems for local drug delivery: Preliminary studies

In situ forming implants (ISFI) are proved to be effective drug delivery systems in various local therapies. This research focuses on preliminary characteristics of a new biodegradable ISFI formulation based on poly(isosorbide succinate) (PISU) for modulated, over 3-week, release of doxycycline hyclate (DOXY). The Alamar Blue cytotoxicity assay was carried out for PISU using FK-1 and AoSMC cell lines. PISU resin was found to be non-toxic in wide range of concentrations. The formulation viscosity, dependent on shear rate, facilitates its easy injection into required site where solid depot is formed immediately after injection. DOXY, incorporated into this formulation, was released in vitro within 21 days, during which collected solutions exhibited antibacterial activity against gram-positive and gram-negative bacteria Staphylococcus aureus and Escherichia coli, respectively. The morphology of the precipitated depots was characterized by scanning electron microscopy (SEM). The obtained results suggest potential applicability of this new PISU-based formulation as injectable drug delivery system forming implant at an injection site by phase separation and precipitation of the polymer.

Physical key properties of antibiotic-free, PLGA/HPMC-based in-situ forming implants for local periodontitis treatment

In-situ forming implants (ISFI) offer an interesting potential for the treatment of periodontitis, allowing for time-controlled drug release directly at the site of action (which is difficult to reach). For this purpose, ISFI loaded with antibiotics have been reported in the literature. But the use of antibiotic drugs at low doses over prolonged periods of time can lead to the development of bacterial resistances. This risk should be avoided. The aim of this study was to develop a novel type of in-situ forming implants, loaded with the antiseptic drug chlorhexidine. Special emphasis was placed on the physical properties of the systems, assuring a reliable residence time in the periodontal pockets of patients suffering from periodontitis. In particular, the risk of premature, accidental loss of the formulations due to mechanical stress (e.g. during tooth brushing and chewing) was to be reduced. Two commercially available drug products for local periodontitis treatment were studied for reasons of comparison: Chlo-site and Parocline. The syringeability and swelling behavior of the formulations were investigated, and the hardness, springiness, resilience and “stickiness” of the systems determined using extracted human teeth. Interestingly, the novel in-situ forming implants, based on PLGA/HPMC and being free of antibiotics, exhibit highly promising physical key properties: They are intensively sticking to teeth’ surfaces and provide adequate mechanical strength to assure reliable and prolonged residence times in periodontal pockets. In contrast, the commercial drug products showed limited adhesion and either rapidly shrank (Chlo-site), or substantially swelled and were mechanically very weak (Parocline).

Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.

An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.

Macroporous acrylamide phantoms improve prediction of in vivo performance of in situ forming implants

In situ forming implants (ISFIs) have shown promise as a sustained, local drug delivery system for therapeutics in a variety of applications. However, development of ISFIs has been hindered by poor correlation between in vitro study results and in vivo performance. In contrast to oral dosage forms, there is currently no clear consensus on a standard for in vitro drug dissolution studies for parenteral formulations. Recent studies have suggested that the disparity between in vivo and in vitro behavior of phase-inverting ISFIs may be, in part, due to differences in injection site stiffness. Accordingly, this study aimed to create acrylamide-based hydrogel phantoms of varying porosity and stiffness, which we hypothesized would better predict in vivo performance. Implant microstructure and shape were found to be dependent on the stiffness of the phantoms, while drug release was found to be dependent on both phantom porosity and stiffness. Specifically, SEM analysis revealed that implant porosity and interconnectivity decreased with increasing phantom stiffness and better mimicked the microstructure seen in vivo. Burst release of drug increased from 31% to 43% when in standard acrylamide phantoms vs macroporous phantoms (10kPa), improving the correlation to the burst release seen in vivo. Implants in 30kPa macroporous phantoms had the best correlation with in vivo burst release, significantly improving (p<0.05) the burst release relative to in vivo from 64%, using a standard PBS dissolution method, to 92%. These findings confirm that implant behavior is affected by injection site stiffness. Importantly, with appropriate optimization and validation, hydrogel phantoms such as the one investigated here could be used to improve the in vitro-in vivo correlation of in situ forming implant formulations and potentially augment their advancement to clinical use.

In situ-forming PLGA implants loaded with leuprolide acetate/β-cyclodextrin complexes: mathematical modelling and degradation

Drug release mechanism of in situ-forming implants (ISIs) based on poly(lactic acid-co-glycolic acid) (PLGA) loaded with leuprolide acetate/β-cyclodextrin (LA/β-CD) complexes via fitting with four diffusion-based semi-empirical models were studied. The release rate constants and release exponent of ISIs were calculated. The main drug release mechanism was Fickian diffusion. The LA diffusion coefficient and release constant were decreased via increasing the portion of β-CD in complexes. The release curve was parabolic, with a higher initial slope and then consistent with the exponential. All ISIs containing LA/β-CD complexes better fitted with the Korsmeyer–Peppas, Weibull and Peppas–Sahlin models rather than first-order model. Furthermore, the effect of LA/β-CD complexation on the degradation of ISIs was studied through scanning electron microscopy (SEM). Results showed that hydrophilic nature of β-CD facilitated the surface erosion of PLGA chains, however after 18 d, ISI-1/10 had still a proper structural strength, due to no hydrolytic degradation of β-CD in this implant.

Nondestructive Characterization of Biodegradable Polymer Erosion in Vivo Using Ultrasound Elastography Imaging.

Significant advancements in biodegradable polymeric materials have been made for numerous biomedical applications including tissue engineering, regenerative medicine, and drug delivery. The functions of these polymers within each application often rely on controllable polymer degradation and erosion, yet the process has proven difficult to measure in vivo. Traditional methods for investigating polymer erosion and degradation are destructive, hampering accurate longitudinal measurement of the samples in the same subject. To overcome this limitation, we have utilized ultrasound elastography imaging as a tool to nondestructively measure strain of poly(lactic-co-glycolic acid) (PLGA) phase sensitive in situ forming implants (ISFI), which changes with progressive loss of structural integrity resulting from polymer erosion. Using this tool, we investigated erosion kinetics of implants comprised of three different PLGA molecular weights (18, 34, and 52 kDa) in vitro and in vivo. The in vitro environment was created using a novel polyacrylamide based tissue mimicking phantom while the in vivo experiment was performed subcutaneously using a rat abdominal model. A strong linear relationship independent of polymer molecular weight was found between average strain values and erosion values in both the in vitro and in vivo environment. Results support the use of a mechanical stiffness-based predicative model for longitudinal monitoring of material erosion and highlight the use of ultrasound elastography as a nondestructive tool for measuring polymer erosion kinetics.

Ultrasound-Guided Intratumoral Delivery of Doxorubicin from in Situ Forming Implants in a Hepatocellular Carcinoma Model

Hepatocellular carcinomas are frequently nonresponsive to systemically delivered drugs. Local delivery provides an alternative to systemic administration, maximizing the dose delivered to the tumor, achieving sustained elevated concentrations of the drug, while minimizing systemic exposure. Ultrasound-guided deposition of doxorubicin (Dox)-eluting in situ forming implants (ISFI) in an orthotopic tumor model significantly lowers systemic drug levels. As much as 60 µg Dox/g tumors were observed 21 days after ISFI injection. Tumors treated with Dox implants also showed a considerable reduction in progression at 21 days. Dox-eluting ISFIs provide a promising platform for the treatment of hepatocellular carcinomas by which drug can be delivered directly into the lesion, bypassing distribution and elimination by the circulatory system.